Nitric oxide, a ubiquitous molecule found throughout the natural world, is a key molecule implicated in many central and benefic molecular pathways and has a well-established role in the function of the central nervous system, as numerous studies have previously shown. Dysregulation of its metabolism, mainly the upregulation of nitric oxide production, has been proposed as a trigger and/or aggravator for many neurological affections. Increasing evidence supports the implication of this molecule in prevalent neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s disease, or amyotrophic lateral sclerosis. The mechanisms proposed for its neurotoxicity mainly center around the increased quantities of nitric oxide that are produced in the brain, their cause, and, most importantly, the pathological metabolic cascades created. These cascades lead to the formation of neuronal toxic substances that impair the neurons’ function and structure on multiple levels. The purpose of this review is to present the main causes of increased pathological production, as well as the most important pathophysiological mechanisms triggered by nitric oxide, mechanisms that could help explain a part of the complex picture of neurodegenerative diseases and help develop targeted therapies.

/pdf/nitric-oxide-nitric-oxide-synthase-system-in-the-1433tpoc.pdf

Nitric Oxide/Nitric Oxide Synthase System in the Pathogenesis of Neurodegenerative Disorders—An Overview

Gasdermin D-executing pyroptosis mediated by NLRP3 inflammasomes has been recognized as a key pathogenesis during stroke. Hydrogen sulfide (H2S) could protect CNS against ischemia/reperfusion (I/R)-induced neuroinflammation, while the underlying mechanism remains unclear. The study applied the middle cerebral artery occlusion/reperfusion (MCAO/R) model to investigate how the brain and the retinal injuries were alleviated in sodium hydrogen sulfide (NaHS)-treated rats. The rats were assigned to four groups and received an intraperitoneal injection of 50 μmol/kg NaHS or NaCl 15 min after surgery. Neurological deficits were evaluated using the modified neurologic severity score. The quantification of pro-inflammatory cytokines, NLRP3, caspase-1, and GSDMD were determined by ELISA and Western blot. Cortical and retinal neurodegeneration and cell pyroptosis were determined by histopathologic examination. Results showed that NaHS rescued post-stroke neurological deficits and infarct progression, improved retina injury, and attenuated neuroinflammation in the brain cortexes and the retinae. NaHS administration inhibits inflammation by blocking the NLRP3/caspase-1/GSDMD pathway and further suppressing neuronal pyroptosis. This is supported by the fact that it reversed the high-level of NLRP3, caspase-1, and GSDMD following I/R. Our findings suggest that compounds with the ability to donate H2S could constitute a novel therapeutic strategy for ischemic stroke.

/pdf/hydrogen-sulfide-attenuates-neuroinflammation-by-inhibiting-izi44pq8.pdf

Hydrogen Sulfide Attenuates Neuroinflammation by Inhibiting the NLRP3/Caspase-1/GSDMD Pathway in Retina or Brain Neuron following Rat Ischemia/Reperfusion

Microglia play key roles in the post-ischemic inflammatory response and damaged tissue removal reacting rapidly to the disturbances caused by ischemia and working to restore the lost homeostasis. However, the modified environment, encompassing ionic imbalances, disruption of crucial neuron-microglia interactions, spreading depolarization, and generation of danger signals from necrotic neurons, induce morphological and phenotypic shifts in microglia. This leads them to adopt a proinflammatory profile and heighten their phagocytic activity. From day three post-ischemia, macrophages infiltrate the necrotic core while microglia amass at the periphery. Further, inflammation prompts a metabolic shift favoring glycolysis, the pentose-phosphate shunt, and lipid synthesis. These shifts, combined with phagocytic lipid intake, drive lipid droplet biogenesis, fuel anabolism, and enable microglia proliferation. Proliferating microglia release trophic factors contributing to protection and repair. However, some microglia accumulate lipids persistently and transform into dysfunctional and potentially harmful foam cells. Studies also showed microglia that either display impaired apoptotic cell clearance, or eliminate synapses, viable neurons, or endothelial cells. Yet, it will be essential to elucidate the viability of engulfed cells, the features of the local environment, the extent of tissue damage, and the temporal sequence. Ischemia provides a rich variety of region- and injury-dependent stimuli for microglia, evolving with time and generating distinct microglia phenotypes including those exhibiting proinflammatory or dysfunctional traits and others showing pro-repair features. Accurate profiling of microglia phenotypes, alongside with a more precise understanding of the associated post-ischemic tissue conditions, is a necessary step to serve as the potential foundation for focused interventions in human stroke.

Role of microglia in stroke.

Astrocytes are increasingly recognised as partaking in complex homeostatic mechanisms critical for regulating neuronal plasticity following central nervous system (CNS) insults. Ischaemic stroke and traumatic brain injury are associated with high rates of disability and mortality. Depending on the context and type of injury, reactive astrocytes respond with diverse morphological, proliferative and functional changes collectively known as astrogliosis, which results in both pathogenic and protective effects. There is a large body of research on the negative consequences of astrogliosis following brain injuries. There is also growing interest in how astrogliosis might in some contexts be protective and help to limit the spread of the injury. However, little is known about how astrocytes contribute to the chronic functional recovery phase following traumatic and ischaemic brain insults. In this review, we explore the protective functions of astrocytes in various aspects of secondary brain injury such as oedema, inflammation and blood-brain barrier dysfunction. We also discuss the current knowledge on astrocyte contribution to tissue regeneration, including angiogenesis, neurogenesis, synaptogenesis, dendrogenesis and axogenesis. Finally, we discuss diverse astrocyte-related factors that, if selectively targeted, could form the basis of astrocyte-targeted therapeutic strategies to better address currently untreatable CNS disorders.

Astrocytes in functional recovery following central nervous system injuries.

Studies have reported that miR-204-5p is involved in multiple biological processes. However, little is known about the expression and mechanism of miR-204-5p in cerebral ischemia and reperfusion injury. This study found that miR-204-5p expression was significantly downregulated in the blood of patients with ischemic stroke, MCAO/R rat brains, and OGD/R neurons. Overexpression of miR-204-5p markedly reduced infarct volume and neurological impairment and alleviated the inflammatory response in vivo. miR-204-5p promoted neuronal viability and reduced apoptotic cells in vitro. Mechanically, miR-204-5p was negatively regulated by the expression lncRNA TUG1 upstream and down-regulated COX2 expression downstream. Therefore, the TUG1/miR-204-5p/COX2 axis was involved in ischemia and reperfusion-induced neuronal damage. This finding may provide a novel strategy for the treatment of cerebral ischemia and reperfusion injury. 

/pdf/mir-204-5p-is-sponged-by-tug1-to-aggravate-neuron-damage-34ypdjop.pdf

miR-204-5p is sponged by TUG1 to aggravate neuron damage induced by focal cerebral ischemia and reperfusion injury through upregulating COX2

Ischemic stroke is associated with increasing morbidity and has become the main cause of death and disability worldwide. Cerebral edema is a serious complication arising from ischemic stroke. It causes an increase in intracranial pressure, rapid deterioration of neurological symptoms, and formation of cerebral hernia, and is an important risk factor for adverse outcomes after stroke. To date, the detailed mechanism of cerebral edema after stroke remains unclear. This limits advances in prevention and treatment strategies as well as drug development. This review discusses the classification and pathological characteristics of cerebral edema, the possible relationship of the development of cerebral edema after ischemic stroke with aquaporin 4, the SUR1-TRPM4 channel, matrix metalloproteinase 9, microRNA, cerebral venous reflux, inflammatory reactions, and cerebral ischemia/reperfusion injury. It also summarizes research on new therapeutic drugs for post-stroke cerebral edema. Thus, this review provides a reference for further studies and for clinical treatment of cerebral edema after ischemic stroke.

/pdf/cerebral-edema-after-ischemic-stroke-pathophysiology-and-2pe59pf1.pdf

Cerebral edema after ischemic stroke: Pathophysiology and underlying mechanisms

Millions of patients are suffering from ischemic stroke, it is urgent to figure out the pathogenesis of cerebral ischemia–reperfusion (I/R) injury in order to find an effective cure. After I/R injury, pro-inflammatory cytokines especially interleukin-1β (IL-1β) upregulates in ischemic brain cells, such as microglia and neuron. To ameliorate the inflammation after cerebral I/R injury, nucleotide-binding oligomerization domain (NOD), leucine-rich repeat (LRR), and pyrin domain-containing protein 3 (NLRP3) inflammasome is well-investigated. NLRP3 inflammasomes are complicated protein complexes that are activated by endogenous and exogenous danger signals to participate in the inflammatory response. The assembly and activation of the NLRP3 inflammasome lead to the caspase-1-dependent release of pro-inflammatory cytokines, such as interleukin (IL)-1β and IL-18. Furthermore, pyroptosis is a pro-inflammatory cell death that occurs in a dependent manner on NLRP3 inflammasomes after cerebral I/R injury. In this review, we summarized the assembly and activation of NLRP3 inflammasome; moreover, we also concluded the pivotal role of NLRP3 inflammasome and inhibitors, targeting the NLRP3 inflammasome in cerebral I/R injury.

https://www.frontiersin.org/articles/10.3389/fnmol.2022.847440/pdf

NLRP3 Inflammasome Activation: A Therapeutic Target for Cerebral Ischemia–Reperfusion Injury

Transient global cerebral ischemia (tGCI) induces inflammation leading to secondary brain injury. Data suggested that cyclooxygenase-2 (COX-2) is involved in the occurrence and development of infla...

Parecoxib exhibits anti-inflammatory and neuroprotective effects in a rat model of transient global cerebral ischemia

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Cerebral edema after ischemic stroke: Pathophysiology and underlying mechanisms

NLRP3 Inflammasome Activation: A Therapeutic Target for Cerebral Ischemia–Reperfusion Injury

Parecoxib exhibits anti-inflammatory and neuroprotective effects in a rat model of transient global cerebral ischemia